Specific aims of this research are the study of new experimental directions for successful elimination of malignant hematological disorders, particularly of B-cell leukemia/lymphoma variants. The tumor model used was the spontaneous BALB/c murine B-cell leukemia (BCL1) described by Slavin and Strober. This tumor model resembles the malignant human prolymphocytic leukemia/lymphoma. Inoculation of BALB/c mice or their F1 hybrids with BCL1 causes enormous splenomegaly (x50), leukemia (up to 500,000 B-lymphocytes per mm in the peripheral blood) and death in 100% of recipients. Mice carrying BCL1 were successfully treated by total lymphoid irradiation (TLI), cyclophosphamide and allogeneic bone marrow (BM) transplantation. Long-term survivors were examined for residual BCL1 cells and for the ability to adoptively transfer graft versus leukemia (GVL) activity. TLI results in potent immunosuppression, reduces tumor load and results in generation of specific and non-specific suppressor cells. TLI permits successful engraftment of histoincompatible marrow allografts without overt graft versus host disease (GVHD). Our data suggest that imcompatible, unlike syngeneic, cells exert a potent GVL effect without GVHD in mice showing bilateral tolerance of host to graft and graft to host. Residual BCL1 cells could not be detected in the allogeneic BM chimeras (greater than 14 to 16 months), using indirect immunofluorescent staining with anti-idiotypic antibody. However, residual tumor cells were present in 50% of the "cured" chimeric mice since adoptive transfer of 1 million spleen cells from 50% of the treated chimeras caused leukemia in BALB/c recipients. In order to determine whether leukemia had been prevented in the chimeras by a persistent cell-mediated mechanism, BALB/c mice were injected with spleen cells from the cured BM chimeras together with BCL1 cells. Onset of leukemia was delayed or completely abolished in a significant proportion of recipients receiving the cell mixtures, suggesting the presence of antitumor immunity in the cured mice. The data suggest that a persistent active immune mechanism may be responsible, in part, for the significant antileukemic effects observed in mice tolerant to donor alloantigens.